Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis

Abstract

Objective: Uncontrolled studies of mesenchymal stem cells (MSCs) in multiple sclerosis suggested some beneficial effect. In this randomized, double-blind, placebo-controlled, crossover phase II study we investigated their safety and efficacy in relapsing-remitting multiple sclerosis patients. Efficacy was evaluated in terms of cumulative number of gadolinium-enhancing lesions (GEL) on magnetic resonance imaging (MRI) at 6 months and at the end of the study.

Methods: Patients unresponsive to conventional therapy, defined by at least 1 relapse and/or GEL on MRI scan in past 12 months, disease duration 2 to 10 years and Expanded Disability Status Scale (EDSS) 3.0-6.5 were randomized to receive IV 1-2×10(6) bone-marrow-derived-MSCs/Kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. Immunological tests were explored to assess the immunomodulatory effects.

Results: At baseline 9 patients were randomized to receive MSCs (n = 5) or placebo (n = 4). One patient on placebo withdrew after having 3 relapses in the first 5 months. We did not identify any serious adverse events. At 6 months, patients treated with MSCs had a trend to lower mean cumulative number of GEL (3.1, 95% CI = 1.1-8.8 vs 12.3, 95% CI = 4.4-34.5, p = 0.064), and at the end of study to reduced mean GEL (-2.8±5.9 vs 3±5.4, p = 0.075). No significant treatment differences were detected in the secondary endpoints. We observed a non-significant decrease of the frequency of Th1 (CD4+ IFN-γ+) cells in blood of MSCs treated patients.

Conclusion: Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties. ClinicalTrials.gov NCT01228266.

Conflict of interest statement

Competing Interests: SL, MS, YB, PM, BM, JB, IG, EMH, NSV, JAA, JA, BF, SB, BSD and FG have nothing to declare. PV has received consultancy fees from Novartis, Roche, Neurotek, Heidelberg Engineering, Digna Biotech, Bionure and TFS and research grants from Novartis, Roche and Digna Biotech, and is founder and holds stocks in Bionure. AS has received compensation for consulting services and speaking from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd and Novartis. Dr. Pablo Villoslada, co-author of the paper, is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

Figures

Figure 1. Study profile.

Figure 2. Relapses and gadolinium-enhancing lesions during the study.

Abbreviations: GEL  =  gadolinium-enhancing lesions; MSCs  =  mesenchymal stem cells; NA  =  not available; Scr  =  screening.

Figure 3. Effects of MSCs in T and B cell population frequency in blood.

Results are shown as percentages respect to the referring cell population (Th1, Th17, CD19 and Treg) and not referred to the total lymphocyte counts. Treatment with mesenchymal stem cells showed a non-significant decrease of the Th1/Th17 populations, increase in regulatory B cells (B reg) population and no changes regarding natural (Nat T reg) and induced (Ind T reg) regulatory T cells populations. Percentage of each population is shown in the graphics regarding the type of therapy, placebo (P) or mesenchymal stem cells (MSCs) and period of treatment, 1 (first period, from month 0 to month 6) or 2 (second period, from month 6 to 12 months).